IL-15 and IFN-γ signal through the ERK pathway to inhibit HCV replication, independent of type I IFN signaling. (December 2019)

• Record Type: Journal Article
• Authors: Vahedi, Fatemeh; Lee, Amanda J.; Collins, Susan E.; Chew, Marianne V.; Lusty, Evan; Chen, Branson; Dubey, Anisha; Richards, Carl D.; Feld, Jordan J.; Russell, Rodney S.; Mossman, Karen L.; Ashkar, Ali A.
• Is Part Of: Cytokine. Volume 124(2019)
• Publication Date: 2019-12
• Subjects: Antiviral agents -- Hepatitis C -- Interferon type I -- Interleukin-15 (IL-15) -- MAP kinase signaling system -- Natural killer (NK) cells; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2018.06.006
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: IFN-γ and IL-15 inhibit HCV replication in Huh7.5 cells. IL-15 and IFN-γ do not induce anti-HCV effects via the type I IFN signaling pathway. IL-15 and IFN-γ do not induce anti-HCV effects via nitric oxide production. IL-15 and IFN-γ may provide protection against HCV via the ERK pathway. Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti HCV effects of IL-15 and IFN-γ. Abstract: Despite effective new treatments for Hepatitis C virus (HCV) infection, development of drug resistance, safety concerns and cost are remaining challenges. More importantly, there is no vaccine available against hepatitis C infection. Recent data suggest that there is a strong correlation between spontaneous HCV clearance and human NK cell function, particularly IFN-γ production. Further, IL-15 has innate antiviral activity and is also one of the main factors that activates NK cells to produce IFN-γ. To examine whether IL-15 and IFN-γ have direct antiviral activity against HCV, Huh7.5 cells were treated with either IFN-γ or IL-15 prior to HCV infection. Our data demonstrate that IFN-γ and IL-15 block HCV replication in vitro . Additionally, we show that IL-15 and IFN-γ do not induce anti-HCV effects through the type I interferon signaling pathway or nitric oxide (NO) production. Instead, IL-15 and IFN-γ provide protection against HCV via the ERK pathway. Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti-HCV effects of IL-15 and IFN-γ and overexpression of ERK1 prevented HCV replication compared to control transfection. Our in vitro data support the hypothesis that early production of IL-15 and activation of NK cells in the liver lead to control of HCV replication.